Phosphorylation of TRPV1 S801 contributes to modality-specific hyperalgesia in mice

John Joseph, Lintao Qu, Sheng Wang, Martin Kim, Daniel Bennett, Jin Ro, Michael J. Caterina, Man Kyo Chung

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Transient receptor potential vanilloid subtype 1 (TRPV1) is a nonselective cationic channel activated by painful stimuli such as capsaicin and noxious heat, and enriched in sensory neurons of the pain pathway. During inflammation, chemical mediators activate protein kinases (such as PKC) that phosphorylate TRPV1 and thereby enhance its function, with consequent increases in nociceptor sensitization. However, the causal relationships between TRPV1 phosphorylation and pathological pain remain unexplored. To directly investigate the roles of one specific TRPV1 phosphorylation event in vivo, we genetically altered a major PKC phosphorylation site, mouse TRPV1 S801, to alanine. The TRPV1 expression pattern in sensory neurons of S801A knock-in (KI) mice was comparable to that in WT controls. However, sensitization of capsaicin-mediated currents after the activation of PKC was substantially impaired in sensory neurons from KI mice. Thermal hyperalgesia induced by PMA or burn injury in KI was identical to WT. Inflammatory thermal hyperalgesia was only marginally attenuated in KI mice. In contrast, PMA-evoked nocifensive responses and sensitization of capsaicin responses were significantly attenuated in the hindpaws of KI mice. Ongoing pain from inflamed masseter muscle was also reduced in KI mice, and was further inhibited by the TRPV1 antagonist AMG9810. These results suggest that PKC-mediated phosphorylation of TRPV1 S801 contributes to inflammation-mediated sensitization of TRPV1 to ligand, but not heat, in vivo. Further, this suggests that interference with TRPV1 S801 phosphorylation might represent one potential way to attenuate inflammatory pain, yet spare basal sensitivity and produce fewer side effects than more general TRPV1 inhibition.

Original languageEnglish (US)
Pages (from-to)9954-9966
Number of pages13
JournalJournal of Neuroscience
Volume39
Issue number50
DOIs
StatePublished - Dec 11 2019

Keywords

  • Inflammation
  • Mouse genetics
  • Pain
  • Phosphorylation
  • Protein kinase C
  • TRPV1

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint

Dive into the research topics of 'Phosphorylation of TRPV1 S801 contributes to modality-specific hyperalgesia in mice'. Together they form a unique fingerprint.

Cite this